Faculty Bibliography

Heart failure is prevalent in those with type 2 diabetes and chronic kidney disease and is associated with significant mortality and morbidity. In the CREDENCE trial canagliflozin reduced the risk of hospitalization for heart failure (HHF) or cardiovascular (CV) death by 31%. In this current analysis we sought to determine whether the effect of canagliflozin on HHF/CV death differed in subgroups defined by key baseline participant characteristics. Cox regression models were used to estimate hazard ratios and 95% confidence intervals. Canagliflozin was associated with a reduction in the relative risk of HHF/CV death regardless of age, sex, history of HF or CV disease, and the use of loop diuretics or GLP1 receptor agonists (all p_interaction >0.114). The absolute benefit of canagliflozin was greater in those at highest baseline risk, such as those with CV disease (50 fewer events/1000 patients treated over 2.5years versus 20 fewer events in those without CV disease) or advanced kidney disease (eGFR 30-45 ml/min/1.73m² : 61 events prevented/1000 patients treated over 2.5 years versus 23 events in eGFR 60-90 ml/min/1.73m² ). Canagliflozin consistently reduces the proportional risk of HHF/CV death across a broad range of subgroups with greater absolute benefits in those at highest baseline risk. This article is protected by copyright. All rights reserved.

Introduction/UNASSIGNED:Relative impacts of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) on mortality and end-stage kidney disease (ESKD) in chronic kidney disease (CKD) are uncertain. Methods/UNASSIGNED:Data from Massachusetts residents with CKD undergoing CABG or PCI from 2003 to 2012 were linked to the United States Renal Data System. Associations with death, ESKD, and combined death and ESKD were analyzed in propensity score-matched multivariable survival models. Results/UNASSIGNED:We identified 6805 CABG and 17,494 PCI patients. Among 3775 matched-pairs, multi-vessel disease was present in 97%, and stage 4 CKD was present in 11.9% of CABG and 12.2% of PCI patients. One-year mortality (CABG 7.7%, PCI 11.0%) was more frequent than ESKD (CABG 1.4%, PCI 1.7%). Overall survival was improved and ESKD risk decreased with CABG compared to PCI, but effects differed in the presence of left main disease and prior myocardial infarction (MI). Survival was worse following PCI than following CABG among patients with left main disease and without MI (hazard ratio = 3.7, 95% confidence interval = 1.3-10.5). ESKD risk was higher with PCI for individuals with left main disease and prior infarction (hazard ratio = 8.1, 95% confidence interval = 1.7-39.2). Conclusion/UNASSIGNED:Risks following CABG and PCI were modified by left main disease and prior MI. In individuals with CKD, survival was greater after CABG than after PCI in patients with left main disease but without MI, whereas ESKD risk was lower with CABG in those with left main and MI. Absolute risks of ESKD were markedly lower than for mortality, suggesting prioritizing mortality over ESKD in clinical decision making.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Prasugrel and ticagrelor have superior efficacy compared with clopidogrel in moderate CKD but have not been studied in kidney failure. The study objective is to determine the effectiveness and safety of prasugrel and ticagrelor in kidney failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:This retrospective cohort study used United States Renal Data System data from 2012 to 2015. We identified all patients on dialysis who received a drug-eluting stent and were alive at 90 days after stent implantation. Inverse probability-weighted Cox proportional hazard models were used. Weights were estimated with propensity scores for multiple treatments. RESULTS:=0.98). A numerically higher incidence of clinically relevant bleeding was seen with prasugrel or ticagrelor compared with clopidogrel (weighted hazard ratio, 1.15; 95% confidence interval, 0.95 to 1.38 and weighted hazard ratio, 1.13; 95% confidence interval, 0.91 to 1.40, respectively). CONCLUSIONS:Prasugrel or ticagrelor does not seem to be associated with significant benefits compared with clopidogrel in patients with kidney failure treated with drug-eluting stents. PODCAST/UNASSIGNED:This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_04_02_CJN12120720.mp3.

BACKGROUND:People with type 2 diabetes and chronic kidney disease experience a high burden of hypertension, but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population are uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP-lowering therapy is also unknown. METHODS:The CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) randomized people with type 2 diabetes and chronic kidney disease to canagliflozin or placebo. In a post hoc analysis, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP-lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mm Hg while receiving ≥3 classes of BP-lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups. RESULTS:interaction ≥0.35), as were effects on other key kidney, cardiovascular, and safety outcomes. CONCLUSIONS:In people with type 2 diabetes and chronic kidney disease, canagliflozin lowers systolic BP across all BP-defined subgroups and reduces the need for additional BP-lowering agents. These findings support use of canagliflozin for end-organ protection and as an adjunct BP-lowering therapy in people with chronic kidney disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791.

Background Coronary revascularization provides important long-term clinical benefits to patients with high-risk presentations of coronary artery disease, including those with chronic kidney disease. The cost-effectiveness of coronary interventions in this setting is not known. Methods and Results We developed a Markov cohort simulation model to assess the cost-effectiveness of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with chronic kidney disease who were hospitalized with acute myocardial infarction or unstable angina. Model inputs were primarily drawn from a sample of 14 300 patients identified using the Medicare 20% sample. Survival, quality-adjusted life-years, costs, and cost-effectiveness were projected over a 20-year time horizon. Multivariable models indicated higher 30-day mortality and end-stage renal disease with both PCI and CABG, and higher stroke with CABG, relative to medical therapy. However, the model projected long-term gains of 0.72 quality-adjusted life-years (0.97 life-years) for PCI compared with medical therapy, and 0.93 quality-adjusted life-years (1.32 life-years) for CABG compared with PCI. Incorporation of long-term costs resulted in incremental cost-effectiveness ratios of $65 326 per quality-adjusted life-year gained for PCI versus medical therapy, and $101 565 for CABG versus PCI. Results were robust to changes in input parameters but strongly influenced by the background costs of the population, and the time horizon. Conclusions For patients with chronic kidney disease and high-risk coronary artery disease presentations, PCI and CABG were both associated with markedly increased costs as well as gains in quality-adjusted life expectancy, with incremental cost-effectiveness ratios indicating intermediate value in health economic terms.

Canagliflozin slows the progression of chronic kidney disease in patients with type 2 diabetes and induces a reversible acute drop in estimated glomerular filtration rate (eGFR), believed to be a hemodynamic effect. Predictors of the initial drop and its association with long-term eGFR trajectories and safety outcomes are unknown. To assess this, we performed a post-hoc analysis of 4289 participants in the CREDENCE trial with type 2 diabetes and chronic kidney disease equally split into treatment and placebo groups who had eGFR measured at both baseline and week three. The eGFR was categorized at week three as greater than a 10% decline; between 0 and 10% decline; and no decline. Long-term eGFR trajectories and safety outcomes were estimated in each category of acute eGFR change by linear mixed effects models and Cox regression after adjustment for baseline characteristics and medications use. Significantly more participants in the canagliflozin (45%) compared to the placebo (21%) group experienced an acute drop in eGFR over 10%. An over 30% drop occurred infrequently (4% of participants with canagliflozin and 2% with placebo). The odds ratio for a drop in eGFR over 10% with canagliflozin compared to placebo was significant at 3.03 (95% confidence interval 2.65, 3.47). Following the initial drop in eGFR, multivariable adjusted long-term eGFR trajectories, as well as overall and kidney safety profiles, in those treated with canagliflozin were similar across eGFR decline categories. Thus, although acute drops in eGFR over 10% occurred in nearly half of all participants following initiation of canagliflozin, the clinical benefit of canagliflozin was observed regardless. Additionally, safety outcomes were similar among subgroups of acute eGFR drop.

Background/UNASSIGNED:There is a paucity of contemporary data examining electrolyte changes during and immediately after hemodialysis (HD), and their relationship with dialysate prescriptions. The present study examines these relationships. Methods/UNASSIGNED:We analyzed patient- (n=66) and HD session-level pre- and post-dialysis laboratory data (n=1,713) over a six-month period from the Monitoring in Dialysis Study. We fit mixed effects regression models to analyze electrolyte, blood urea nitrogen, creatinine, and albumin levels immediately post-HD, accounting for pre-HD and dialysate prescriptions. In a subset of US patients (n=40), 15-minute post-HD and 30-minute post-HD values were available at one session. Predictive models were fit to estimate electrolyte levels immediately post-HD, accounting for pre-HD concentrations and dialysate prescriptions. Results/UNASSIGNED:Serum bicarbonate, calcium, and albumin increased (mean increase 4.9±0.3 mEq/L, 0.7±0.1 mEq/L, and 0.4±0.03 g/dL, respectively), whereas potassium, magnesium, and phosphorus decreased immediately post-HD (mean -1.2±0.1 mEq/L, -0.3±0.03 mEq/L, and -3.0±0.2 mg/dL, respectively). Hypokalemia and hypophosphatemia were present in 40% of and 67% of immediate post-HD samples, respectively. Dynamic changes were observed in electrolyte concentrations at 15- and 30-minutes post-HD, compared to immediately post-HD. Conclusion/UNASSIGNED:We describe the magnitude of post-dialytic changes in serum electrolytes with contemporary HD, reporting a high incidence of electrolyte abnormalities post-HD, and present predictive nomograms relating electrolyte changes immediately post-HD to dialysate prescriptions. Our results may be useful for clinical care and provide insights for future research on dialysate prescriptions.

Introduction/UNASSIGNED:Reports from the United States suggest that acute kidney injury (AKI) frequently complicates COVID-19, but understanding of AKI risks and outcomes is incomplete. Additionally, whether kidney outcomes have evolved during the course of the pandemic is unknown. Methods/UNASSIGNED:We used electronic records to identify COVID-19 patients with and without AKI admitted to 3 New York Hospitals between March 2 and August 25, 2020. Outcomes included AKI overall and according to admission week, AKI stage, the requirement for new renal replacement therapy (RRT), mortality and recovery of kidney function. Logistic regression was utilized to assess associations of patient characteristics and outcomes. Results/UNASSIGNED:Out of 4732 admissions 1386 (29.3%) patients had AKI. Among those with AKI, 717 (51.7%) had Stage 1, 132 (9.5%) Stage 2, 537 (38.7%) stage 3, and 237 (17.1%) required RRT initiation. In March 536/1648 (32.5%) of patients developed AKI compared with 15/87 (17.2%) in August (P<0.001 for monthly trend) whereas RRT initiation was required in 6.9% and 0% of admission, in March and August respectively. Mortality was higher with than without AKI (51.6% vs 8.6%) and was 71.9% in individuals requiring RRT. However, most patients with AKI who survived hospitalization (77%) recovered to within 0.3 mg/dL of baseline creatinine. Among those surviving to discharge, 62% discontinued RRT. Conclusions/UNASSIGNED:AKI impacts a high proportion of admitted COVID-19 patients and is associated with high mortality, particularly when RRT is required. AKI incidence appears to be decreasing over time and kidney function frequently recovers in those who survive.

Background/UNASSIGNED:The intestinal microbiome is an appealing target for interventions in ESKD because of its likely contribution to uremic toxicity. Before conducting clinical trials of microbiome-altering treatments, it is necessary to understand the within-person and between-person variability in the composition and function of the gut microbiome in patients with ESKD. Methods/UNASSIGNED:We conducted a multicenter, nonrandomized, crossover feasibility study of patients on maintenance hemodialysis consisting of three phases: pretreatment (8 weeks); treatment, during which the prebiotic, p-inulin, was administered at a dosage of 8 g twice daily (12 weeks); and post-treatment (8 weeks). Stool samples were collected 1-2 times per week and blood was collected weekly for 28 weeks. The gut microbiome was characterized using 16S ribosomal-RNA sequencing and metabolomic profiling. Results/UNASSIGNED:=0.004) and a progressive decrease in prevalence of high intraclass correlations, indicating an increase in intraparticipant microbiome diversity during and after p-inulin treatment. An effect of p-inulin on the metabolomic profile was not evident. Conclusions/UNASSIGNED:The intraparticipant stability of the gut microbiome under no-treatment conditions, the tolerability of p-inulin, the signals of increased diversity of the microbiome with p-inulin treatment, and the willingness of participants to provide stool samples all support the feasibility of a larger trial to investigate interventions targeting the gut microbiome in patients with ESKD. Whether or not p-inulin has sufficient efficacy as an intervention requires evaluation in larger studies. Clinical Trial registry name and registration number/UNASSIGNED:Gut Microbiome and p-Inulin in Hemodialysis, NCT02572882.